[unreadable] This grant proposes to investigate the potential utility and mechanism of action of fully human monoclonal antibodies (HuMAbs) to the anthrax protective antigen (PA) as prophylactic and therapeutic antitoxins. For immunization, Medarex, Inc. uses its proprietary HuMab mice, which express transgenic human antibody genes and have an inactivated murine antibody locus. These mice produce fully human, affinity-matured antibodies, which are isolated and produced by hybridoma and transfectoma technology. Under a CRADA with USAMRIID and Dartmouth University, Medarex, Inc. has developed a panel of HuMAbs that react with and potently neutralize Anthrax toxin in in vitro cytotoxicity assays, have defined a novel neutralizing epitope on PA-63, and provide protection and therapy in an inhalational anthrax rabbit model. From this panel, 1 monoclonal antibody (mAb 5E8) and 1 backup antibody (5D5) were selected for further development. The HuMAbs were selected based on superior anthrax toxin neutralizing activity in macrophages. The HuMab 5E8 affords extended survival to rabbits after inhalation of a lethal dose of anthrax spores, when administered concurrently with the exposure (prophylaxis / post-exposure prophylaxis activity), and even when given after the onset of clinical signs of anthrax disease (therapeutic activity). The envisioned practical usage of this antibody will be to provide rapid passive immunity to individuals at risk for exposure to Bacillus anthracis and ensuing serious disease. The usage may be prophylactic in pre- or post-exposure situations, but more importantly, may have efficacy in treatment of individuals with active disease for which there is no current effective therapy. To further investigate the utility and mechanisms of action of this antibody, Medarex, Inc. aims to: 1. Further define the specific mechanism(s) of protection conferred by HuMab 5E8 and other anti-PA monoclonal antibodies; 2. Develop current animal models of inhalation anthrax amenable for the investigation of therapeutic activity; 3. Investigate the activity of HuMab 5E8 in therapeutic models of inhalation anthrax; and 4. Investigate the effect of the antibody on the development of natural immunity to infection and on the immunogenicity of the PA vaccine. [unreadable] [unreadable]